Niemann-Pick C disease is an autosomal recessive lysosomal storage disorder for which there is no effective treatment. Patients with this disease exhibit a clinically heterogeneous phenotype characterized by severe, progressive neurological impairment that is usually fatal in childhood. Most cases are caused by loss-of- function mutations in the NPC1 gene, resulting in impaired intracellular trafficking of cholesterol and glycosphingolipids. Disease causing mutations were first identified over a decade ago and the role of NPC1 in cholesterol trafficking is emerging from elegant cell biology studies. Nonetheless, strategies to promote normal intracellular lipid transport have been elusive, and to date, the severe, progressive neurological impairment characteristic of Niemann-Pick C disease remains untreatable. The objective of this application is to identify cellular pathways where interventions could result in effective treatments. Our central hypothesis is that modulating the protein homeostasis network will enable proper folding and trafficking of some NPC1 mutants to produce a functional recovery. This hypothesis springs from our analysis of patient fibroblasts in which the NPC1 gene carries disease-causing missense mutations. Our preliminary studies show that modulating ER calcium levels by treatment with ryanodine receptor antagonists produces a striking recovery of functional NPC1. Further, we demonstrate that patient fibroblasts can be reprogrammed into induced pluripotent stem cells (iPSCs) to obtain patient-specific neurons (hereafter referred to as induced neurons), thereby generating a model system to test biologically active small molecules on the target cells that are critical to neurodegeneration. Cell biological, pharmacological, biochemical and genetic approaches will be used to determine the extent to which modulating ER calcium levels promotes the recovery of functional NPC1 in patient fibroblasts (Aim 1), and to establish that targeting ER protein homeostasis pathways ameliorates the effects of NPC1 deficiency in patient-specific induced neurons (Aim 2). These studies are expected to have an important positive impact by providing proof-of-concept evidence in support of a novel treatment strategy for patients with missense mutations in the NPC1 gene, and demonstrate the utility of iPSC-derived neurons as a model system for therapeutic development.

Public Health Relevance

The relevance of the proposed studies to public health is that they will proof-of-concept evidence in support of a novel treatment strategy for patients with Niemann-Pick type C disease, and will demonstrate the utility of iPSC-derived neurons as a model system for therapeutic development.